This disclosure is directed to ligands that bind to peroxisome proliferator activated receptors (PPAR) .gamma.1 or .gamma.2 and which function as antiproliferative agents. The invention is also directed to the use of PPAR .gamma.1 or .gamma.2 to identify compounds that are antiproliferative agents. This disclosure is further directed to new medical uses of these compounds.
Peroxisome proliferators are a structurally diverse group of compounds that when administered to rodents elicit dramatic increases in the size and number of hepatic and renal peroxisomes, as well as concomitant increases in the capacity of peroxisomes to metabolize fatty acids via increased expression of the enzymes of the beta-oxidation cycle. Compounds of this group include but are not limited to the fibrate class of hyperlipidemic drugs, herbicides and phthalate plasticizers. Peroxisome proliferation is also triggered by dietary or physiological factors such as a high-fat diet and cold acclimatization.
Identification of a member of the nuclear hormone receptor superfamily activated by these chemicals has facilitated analysis of the mechanism by which peroxisome proliferators exert their pleiotropic effects. This receptor, known as peroxisome proliferator activated receptor alpha (PPAR), is activated by a number of medium and long-chain fatty acids. The receptor stimulates expression of genes encoding rat acyl-CoA oxidase and hydratase-dehydrogenase.
The PPAR .gamma. receptor subtypes are involved in activating the program of adipocyte differentiation and are not involved in stimulating peroxisome proliferation in the liver. There are two isoforms of PPAR gamma: PPAR .gamma.1 (PPAR.gamma.1) and PPAR .gamma.2 (PPAR.gamma.2), which differ only in that PPAR.gamma.2 contains an additional 28 amino acids present at the amino terminus. In mice, PPAR.gamma.2 is expressed specifically in fat cells. Tontonoz et al., Cell 79: 1147-1156 [1994] provide evidence to show that one physiological role of PPAR.gamma.2 is to induce adipocyte differentiation. As with other members of the nuclear hormone receptor superfamily, PPAR.gamma.2 regulates the expression of genes through interaction with other proteins and binding to hormone response elements for example in the 5' flanking regions of responsive genes. An example of a PPAR.gamma.2 responsive gene is the tissue-specific adipocyte P2 gene.
Three classes of ligands have been identified for the PPAR.gamma. receptors. Prostaglandin J.sub.2 could represent an endogenous class of ligands (Forman et al. Cell 83: 803-812 [1995], Kliewer et al. Cell 83: 813-819 [1995]), while the thiazolidinediones could represent another class (Lehman et al. J. Biol. Chem 270: 12953-12956 [1995]). A third class of ligands is represented by a new series of MRL compounds. The thiazolidinediones and MRL compounds are antidiabetic compounds effective in reducing glucose, lipid and insulin levels in rodent models. Thus, novel PPAR.gamma. ligands and regulators could be used in the treatment of diabetes and effect fat cell differentiation. In addition, cyclopentanone prostaglandins having structural similarity to Prostaglandin J2 have been described to have antiproliferative and antiviral properties (C. Rozera et al., J. Clin. Invest. 97:1795-1803; M. Santoro et al., J. Gen. Virol. 68:1153-1158; Sasaki and Fukushima, Anti-Cancer Drugs 5:131-138). Other compounds of this class of prostaglandins but the bind to PPAR .gamma. receptor subtypes will also have antiproliferative and antivral properties.